# US 5,705,502 A · Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,705,502 A
- Document ID: US5705502A
- Status: Granted
- Kind: A
- Application number: 08/446,742
- Filed: 1995-05-31
- Granted: 1998-01-06
- Earliest claimed: 1993-10-01
- Assignees: Novartis AG
- Inventors: Jurg Zimmermann
- Web page: https://patentgrep.com/patent/US5705502A

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- A61P 35/00: Antineoplastic agents
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Described are N-phenyl-2-pyrimidineamine derivatives of formula I ##STR1## wherein R.sub.1 is a substituted cyclic radical, the cyclic radical being bonded at a ring carbon atom in each case and being selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.3, --C(.dbd.O)--R.sub.4, --SO.sub.2 --N(R.sub.5)--R.sub.6, --N(R.sub.7)--R.sub.8, --OR.sub.9 and fluorine-substituted lower alkyl, wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and R.sub.2 is selected from halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.10, --C(.dbd.O)--R.sub.11, --SO.sub.2 --N(R.sub.12)--R.sub.13, --N(R.sub.14)--R.sub.15, --OR.sub.16 and fluorine-substituted lower alkyl, wherein R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15 and R.sub.16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino. Those compounds can be used, for example, in the treatment of tumour diseases.

## Claims

### Claim 1

An N-phenyl-2-pyrimidineamine derivative of formula I ##STR9## wherein R.sub.1 is a substituted cyclic radical, the cyclic radical being bonded at a ring carbon atom in each case and being selected from pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.3, --C(.dbd.O)--R.sub.4, --SO.sub.2 --N(R.sub.5)--R.sub.6, --N(R.sub.7)--R.sub.8, --OR.sub.9 and fluorine-substituted lower alkyl, wherein
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and
R.sub.2 is selected from halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.10, --C(.dbd.O)--R.sub.11, --SO.sub.2 --N(R.sub.12)--R.sub.13, --N(R.sub.14)--R.sub.15, --OR.sub.16 and fluorine-substituted lower alkyl, wherein
R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15 and R.sub.16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino, or a salt of such a compound having at least one salt-forming group.

### Claim 2 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is substituted pyridyl bonded to a ring carbon atom, the substituents of the above-mentioned pyridyl radical being selected from halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.3, --N(R.sub.7)--R.sub.8 and --OR.sub.9, wherein
R.sub.3, R.sub.7, R.sub.8 and R.sub.9 are each independently of the others hydrogen or lower alkyl; and
R.sub.2 is selected from halogen, --C(.dbd.O)--OR.sub.10, wherein
R.sub.10 is hydrogen or lower alkyl,
and from fluorine-substituted lower alkyl,
or a salt of such a compound having at least one salt-forming group.

### Claim 3 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is a pyridyl radical substituted by halogen, cyano, carboxy, carbamoyl, hydroxy or by N-lower alkyl-amino, and
R.sub.2 is halogen or fluorine-substituted lower alkyl,
or a salt thereof.

### Claim 4 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is a 4-pyridyl radical substituted in the 2-position with respect to the pyridine nitrogen by chlorine, cyano, carboxy, carbamoyl, hydroxy or by N-propyl-amino and
R.sub.2 is chlorine or trifluoromethyl,
or a salt thereof.

### Claim 5 (depends on 1)

A compound according to claim 1 of formula I, wherein
R.sub.1 is a 4-pyridyl radical substituted in the 2-position with respect to the pyridine nitrogen by chlorine, cyano, carboxy, carbamoyl, hydroxy, amino, N-propyl-amino, N,N-dimethylamino or by N-butyl-amino, and
R.sub.2 is chlorine, trifluoromethyl, carboxy or lower alkoxycarbonyl,
or a salt thereof.

### Claim 6 (depends on 1)

A compound according to claim 1 of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, selected from
N-(3-chloro-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine,
N-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine,
N-(3-trifluoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine,
N-(3-trifluoromethyl-phenyl)-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine,
N-(3-trifluoromethyl-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-n-propylamino-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-amino-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-hydroxy-4-pyridyl)-2-pyrimidineamine,
N-(3-chloro-phenyl)-4-(2-dimethylamino-4-pyridyl)-2-pyrimidineamine,
N-›3-ethoxycarbonyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine,
N-›3-isopropoxycarbonyl-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine,
N-›3-carboxy-phenyl!-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and
N-›3-chloro-phenyl!-4-›2-(n-1-butylamino)-4-pyridyl!-2-pyrimidineamine,
and from the pharmaceutically acceptable salts of such compounds having at least one salt-forming group.

### Claim 7 (depends on 1)

A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, said compound being N-(3-chloro-phenyl)-4-(2-amino-4-pyridyl)-2-pyrimidineamine.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group together with a pharmaceutical carrier.

### Claim 9

A process for the preparation of an N-phenyl-2-pyrimidineamine derivative of formula I ##STR10## wherein R.sub.1 is a substituted cyclic radical, the cyclic radical being bonded at a ring carbon atom in each case and being selected from pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.3, --C(.dbd.O)--R.sub.4, --SO.sub.2 --N(R.sub.5)--R.sub.6, --N(R.sub.7)--R.sub.8, --OR.sub.9 and fluorine-substituted lower alkyl, wherein
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and
R.sub.2 is selected from halogen, cyano, carbamoyl, --C(.dbd.O)--OR.sub.10, --C(.dbd.O)--R.sub.11, --SO.sub.2 --N(R.sub.12)--R.sub.13, --N(R.sub.14)--R.sub.15, --OR.sub.16 and fluorine-substituted lower alkyl, wherein
R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15 and R.sub.16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino, or of a salt of such a compound having at least one salt-forming group, wherein a compound of formula II
R.sub.1 --C(.dbd.O)--CH.dbd.CH--N(R.sub.17)--R.sub.18 (II),
wherein R.sub.17 and R.sub.18 are each independently of the other lower alkyl and R.sub.1 is as defined above, functional groups present in a compound of formula II, with the exception of the groups participating in the reaction, being, if necessary, in protected form, or a salt of such a compound is reacted with a compound of formula III ##STR11## wherein R.sub.2 is as defined above, functional groups present in a compound of formula III, with the exception of the guanidino group participating in the reaction, being, if necessary, in protected form, or with a salt of such a compound, and any protecting groups present are removed
and, if desired, a compound of formula I obtainable in accordance with the above process is converted into its salt, or an obtainable salt of a compound of formula I is converted into the free compound.